Therapeutic applications for the anti-T-BAM (CD40-L) monoclonal antibody 5C8 in the treatment of reperfusion injury in non-transplant recipients

Abstract

Activation of cells bearing CD40 on their cell surface by CD40 ligand is inhibited by contacting the cells with an agent capable of inhibiting interaction between CD40 ligand and the cells, in an amount effective to inhibit activation of the cells. Activation of cells bearing CD40 on their surface by CD40 ligand in a subject is inhibited by administering to the subject an agent capable of inhibiting interaction between CD40 ligand and the cells, in an amount effective to inhibit activation of the cells. Reperfusion injury, in an non-transplant recipient, is a condition associated with CD40 ligand-induced activation of CD40-bearing cells. Therefore, reperfusion injury can be treated by the administration of anti-human CD40L monoclonal antibodies, such as those described herein (e.g. 5c8 mAb).

What is claimed is:  
     
       1. A method for treating reperfusion injury in a subject other than a graft recipient, by inhibiting activation of cells bearing CD40 on their surface, other than B cells, comprising the step of administering to said subject an antibody, Fab, F(ab′)2 or a single chain antibody, which binds specifically to an antigen specifically bound by monoclonal antibody 5c8, produced by the hybridoma having ATCC Accession No. HB 10916, wherein said antibody, Fab, F(ab′)2 or single chain antibody, inhibits binding between CD40 ligand and CD40 on the surface of said cells, wherein said antibody, Fab, F(ab′)2 or single chain antibody, is effective to inhibit transmigration of inflammatory cells across the barrier of endothelial cells in said subject . 
     
     
       2. The method according to  claim 1 , wherein said CD40-bearing cells are selected from the group consisting of: fibroblasts, endothelial cells, epithelial calls, T cells, basophils, macrophages, Reed-Steinberg cells, keratinocytes, dendritic cells, plasma cells and myeloma cells. 
     
     
       3. The method according to  claim 1 , wherein said antibody is a monoclonal antibody or a polyclonal antibody. 
     
     
       4. The method according to  claim 1 , wherein said antibody is selected from the group consisting of: a chimeric antibody, a humanized antibody and an antibody which includes a CDR region from a first human antibody and an antibody scaffold from a second human antibody. 
     
     
       5. The method according to  claim 1 , wherein said antibody is a primatized antibody. 
     
     
       6. The method according to  claim 1 , wherein said antibody is monoclonal antibody 5c8, produced by the hybridoma having ATCC Accession No. HB 10916. 
     
     
       7. The method according to  claim 1 , wherein said antibody is a humanized monoclonal antibody 5c8. 
     
     
       8. The method according to  claim 1 , wherein said antibody is a primatized monoclonal antibody 5c8. 
     
     
       9. The method according to  claim 1 , wherein said Fab has a complementarity determining region of a light chain or a heavy chain. 
     
     
       10. The method according to  claim 1 , wherein said Fab has a variable region of a light chain or a heavy chain. 
     
     
       11. The method according to  claim 1 , wherein said antibody, Fab, F(ab′)2 or single chain antibody, is selected by a screening method, comprising the steps of: 
       (a) isolating a sample of cells comprising CD40-bearing fibroblasts, endothelial cells, epithelial cells, T cells, basophils, macrophages, Reed-Steinberg cells, keratinocytes, dendritic cells, plasma cells or myeloma tells;  
       (b) culturing said sample under conditions permitting activation of CD40-bearing fibroblasts, endothelial cells, epithelial cells, T cells, basophils, macrophages, Reed-Steinberg cells, keratinocytes, dendritic cells, plasma cells or myeloma cells;  
       (c) contacting said sample with:  
       (i) cells expressing a protein which is specifically recognized by monoclonal antibody 5c8, produced by the hybridoma having ATCC Accession No. HB 10916, or  
       (ii) a protein which is specifically recognized by monoclonal antibody 5c8, produced by the hybridoma having ATCC Accession No. 10916,  
       under conditions which permit activation of said CD40-bearing fibroblasts, endothelial cells, epithelial cells, T cells, basophils, macrophages, Reed-Steinberg cells, keratinocytes, dendritic cells, plasma cells or myeloma cells; 
       (d) contacting said sample with an antibody, Fab, F(ab′)2 or single chain antibody, under conditions which permit said antibody, Fab, F(ab′)2 or single chain antibody, to inhibit activation of said CD40-bearing fibroblasts, endothelial cells, epithelial cells, T cells, basophils, macrophages, Reed-Steinberg cells, keratinocytes, dendritic cells, plasma cells or myeloma cells; and  
       (e) determining whether said antibody, Fab, F(ab′)2 or single chain antibody, is capable of inhibiting activation of said CD40-bearing fibroblasts, endothelial cells, epithelial cells, T cells, basophils, macrophages, Reed-Steinberg cells, keratinocytes, dendritic cells, plasma cells or myeloma cells.  
     
     
       12. The method according to  claim 11 , wherein the sample of cells is isolated from a tissue. 
     
     
       13. The method according to  claim 11 , wherein the sample of cells is selected from the group consisting of: a cell line in culture, cells isolated from an animal and cells isolated from a body fluid. 
     
     
       14. The method according to  claim 1 , wherein said subject is a mammal. 
     
     
       15. The method according to  claim 14 , wherein said mammal is a human or a non-human primate. 
     
     
       16. The method according to  claim 1 , wherein said antibody, Fab, F(ab′)2 or single chain antibody, is administered to said subject by a parenteral route. 
     
     
       17. The method according to  claim 1 , wherein said antibody, Fab, F(ab′)2 or single chain antibody, is administered to said subject at intervals ranging from each month to every other month. 
     
     
       18. The method according to  claim 1 , wherein said antibody, Fab, F(ab′)2 or single chain antibody, is administered to said subject dally for the first three days of treatment, after which the antibody, Fab, F(ab′)2 or single chain antibody, is administered once every three weeks. 
     
     
       19. The method according to  claim 1 , wherein said antibody, Fab, F(ab′)2 or single chain antibody, is administered to said subject daily intravenously for the first three days of treatment, after which the antibody, Fab, F(ab′)2 or single chain antibody, is administered subcutaneously or intramuscularly once every week. 
     
     
       20. The method according to  claim 1 , wherein said antibody, Fab, F(ab′)2 or single chain antibody, is administered to said subject parenterally, daily followed by administration of the antibody, Fab, F(ab′)2 or single chain antibody, subcutaneously or intramuscularly once every week. 
     
     
       21. The method according to  claim 1 , wherein said antibody, Fab, F(ab′)2 or single chain antibody, is administered to said subject at a dosage range of between about 0.01 and 200 mg/kg body weight of said subject. 
     
     
       22. The method according to  claim 1 , wherein said antibody, Fab, F(ab′)2 or single chain antibody, is administered to said subject at a dosage range of between 0.01 and 50 mg/kg body weight of said subject. 
     
     
       23. The method according to  claim 1 , wherein said antibody, Fab, F(ab′)2 or single chain antibody, is administered to said subject at a dosage range of between about 1 and 30 mg/kg body weight of said subject.